Estrogen is thought to play an important role in age-related cognitive decline, neuronal plasticity, as well as the pathogenesis of Alzheimer disease (AD). Epidemiological evidence linked decreased incidence of AD and cognitive decline in women previously exposed to hormone (estrogen) replacement therapy (HRT). Further, clinical data correlates estrogen deficiency to the etiology of AD, yet initiating HRT in elderly (age 65 and over) post-menopausal women failed to improve cognitive performance. These findings have led many in the field, including us, to re-examine the role of estrogen in cognition and AD and to look beyond the direct effects of estrogen to more indirect, though perhaps no less important, effects. To this end, declining levels of sex steroids in women and men, albeit to a lesser degree, result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by HRT and serum levels of LH are higher in AD patients compared to aged-matched controls. Moreover, recent published and preliminary data, including our own studies, show that LH is capable of modulating cognitive behavior and associated neuronal plasticity markers, is present in the brain, has the highest levels of receptors in the hippocampus, is increased in the AD brain, and is capable of altering amyloid-b protein precursor processing. In this proposal, our goal is to dissect the hormonal contributions and interactions of estrogen and LH on cognition, synaptic plasticity, and AD pathogenesis using animal models of menopause and AD. Specifically, we propose to measure cognitive behavior [Morris Water Maze (MWM) task], neuronal plasticity as measured by structural and functional changes in synaptic remodeling, and cognitive decline (MWM) and amyloid-b synthesis and deposition in female C57/BLJ6 and AD transgenic mice (Tg2576) after ovariectomy and thereafter assess the effect of a "critical window" of efficacy of pharmacological manipulation of estrogen and LH levels, either singly or in combination. This systematic analysis will not only address the importance of hormonal action in cognition but will also begin to dissect the individual contributions of estrogen and LH and how these aspects are affected by the post-menopausal timing of HRT. PUBLIC HEALTH RELEVANCE: Postmenopausal changes in HPG-axis hormones, in particular estrogen, is tightly linked to cognitive impairment in older individuals and development of AD. This proposal trascends beyond the study of estrogen to determine the influence of other HPG-axis hormones. Specifically, the objective of this body of work is to investigate whether luteinizing hormone is a central mediator of such impairment, independently or in conjunction with estrogen. Outcomes of the proposal are not only important from a scientific perspective but could lead to immediate novel therapeutic regimens.